Patent RU-2697707-C9 (RU)
Title: Processes for preparing dihydropyrimidine derivatives and intermediate products thereof
Inventor: REN QINGYUN
IPC: C07D417/14
Filed: 2014-11-27
Granted: 2019-10-03
Abstract: FIELD: chemistry. 
     SUBSTANCE: invention relates to versions of a novel method of producing a dihydropyrimidine derivative of formula (I-2) or a tautomer thereof of formula (Ia-2). Invention also relates to a novel intermediate product for synthesis thereof of formula (V-2) for getting  compound of formula (I-2) or its tautomer of formula (Ia-2). Compounds of formula (I-2) and formula (Ia-2) can be used for treating or relieving viral infection, particularly HBV infection, or diseases caused by HBV infection. Process of preparing a dihydropyrimidine compound of formula (I-2) or a tautomer thereof of formula (Ia-2)  
     
       
     
     (I-2) or (Ia-2), where each R 1  is F; R 2  is Cl or Br; R 3  is C 1-4  alkyl; Z is -S-; Y is -O-, -S-, -S(=O) t , -(CH 2 ) q - or -N(R 5 )-; each t and q independently has value of 0, 1 or 2; R 5  is H or C 1-4  alkyl; each R 6  independently represents H, halo, C 1-4  alkyl, C 1-4  haloalkyl, amine, C 1-4  alkylamine, C 1-4  alkoxy, nitro, triazolyl, tetrazole, -(CR 7 R 7a ) m -OH, -S(=O) q OR 8a , -(CR 7 R 7a ) m -S(=O) q N(R 8a ) 2 , -(CR 7 R 7a ) t -N(R 8a ) 2 , -(CR 7 R 7a ) m -C(=O)O-R 8 , -(CR 7 R 7a ) m -C(=O)O-(CR 7 R 7a ) m -OC(=O)O-R 8 , -(CR 7 R 7a ) m -C(=O)O-(CR 7 R 7a ) m -OC(=O)-R 8 , -(CR 7 R 7a ) m -C(=O)O-(CR 7 R 7a ) m -C(=O)O-R 8 , -(CR 7 R 7a ) m -OC(=O)-R 8  or -(CR 7 R 7a ) m -C(=O)-N(R 8 R 8a ); each R 7a  and R 7  independently represents H, halo, C 1-4  alkyl, C 1-4  haloalkyl, -(CH 2 ) m -OH or -(CH 2 ) m -C(=O)OR 8 ; each R 8  and R 8a  independently represents H, C 1-4  alkyl, amino-C 1-4 -alkyl, C 1-4  alkoxy, C 1-6  alkyl-S(=O) q -, C 6-10  aryl, C 1-9  heteroaryl, C 3-6  cycloalkyl, C 2-9  heterocyclyl, C 6-10  aryl-C 1-6 -alkyl, C 1-9  heteroaryl-C 1-6 -alkyl, C 3-6  cycloalkyl-C 1-4 -alkyl, C 2-9  heterocyclyl-C 1-6 -alkyl, C 2-9  heterocyclyl-S(=O) q -, C 1-9  heteroaryl-S (=O) q -, C 3-6  cycloalkyl-S(=O) q -, C 6-10  aryl-S(=O) q -, -(CH 2 ) m -OH, -(CH 2 ) m -C(=O)O-(CH 2 ) m -H or -(CH 2 ) m -OC(=O)-(CH 2 ) m -H; n takes values of 0, 1, 2, 3, 4 or 5; each m independently assumes values of 0, 1, 2, 3 or 4; consists of following steps: step (A): reacting an amidine compound with formula (II-1) 
       , 
     or a salt thereof, and an aldehyde compound of formula (III-2) 
     
       
     
     and compounds with formula (IV) 
       , 
     to obtain a compound of formula (V-2)  
     
       
     
     where R 1  independently represents F; R 2  is Cl or Br; R 3b  is isopropoxy; R 3a  is H; Z is -S-; wherein reaction at step (A) is carried out at temperature from 25 to 154 °C, wherein step (A) further comprises cooling the compound of formula (V-2) obtained at step (A) to obtain a solid compound of formula (V-2) to a cooling temperature in the range of from -40 to 40 °C, step (B) comprises halogenating a compound of formula (V-2) to form a halide; and then reacting a halide and a compound of formula (VI) 
     
       
     
     or a salt thereof, to obtain a compound of formula (VII-2) 
     
       
     
     and step (C) consists in obtaining a compound of formula (I-2) or formula (Ia-2) from compound of formula (VII-2) by re-esterification, where re-esterification step is carried out in presence of base. Either a compound of formula (I-2) or a tautomer thereof of formula (Ia-2) is obtained by a method involving step (1) involving reaction of compound 
        and    
     and    
     to obtain compound 
     
       
     
     where R 3b  is isopropoxy; and R 3a  is H, R 1  is F; R 2  is Cl or Br; Z is -S-; wherein reaction at step (1) is carried out under conditions as described above for step A, then, step (2) is carried out: forming a compound of formula (X-2) from a compound of formula (V-2) by re-esterification, wherein the re-esterification step is carried out in the presence of base    
     and step (3): halogenation of compound with formula (X-2) to form halide; and then reacting halide and a compound of formula (VI) 
     
       
     
     or a salt thereof, to obtain a compound of formula (I-2) or formula (Ia-2). Values of radicals R 1 , R 2 , R 3 , R 6 , Y, Z are given above. 
     EFFECT: disclosed process is simple by mechanism of action, reduces total time of process, provides high output of end product (up to 78 %) and convenient separation of finished product, which is suitable for industrial production. 
     20 cl, 22 tbl, 12 ex